Trace amounts of most metals, including nickel, are required for adequate human health. However, excesses of these metals can result in toxic effects. The toxicological effects of nickel to mammals and particularly to humans has been documented since the middle of the fifteenth century when German miners were noted to have high levels of lung disorders (Sunderman, (1989) Annals of Clin. Lab. Science 19(1): 1-16). Beginning in 1884 with T. P. Anderson Stuart, systematic studies have been conducted on the toxicology of nickel so that excessive nickel is now recognized as a major contributing factor to many mammalian disorders. For example, nickel poisoning has been implicated in pneumonitis with adrenal cortical insufficiency, abnormal hyaline membrane formation, pulmonary edema and hemorrhage, hepatic degeneration, brain and renal congestion, cancer of the respiratory tract, pulmonary eosinophilia, asthma, primary irritant dermatitis, allergic dermatitis urticaria, eczema, allergenic reactions, osteomyelitis, osteonecrosis, etc. (Sunderman, (1989) Annals of Clin. Lab. Science 19(1): 1-16; Louria et al., (1972) Annals of Internal Medicine 76:307-319). In addition, nickel has been hypothesized to increase vasoconstriction during myocardial infarction (Rubanyi et al., (1981) J. Mol. Cellular Cardiology 13:1023-1026; Rubanyi et al., (1981) Ann. Clin. Lab. Sci. 11(1):93) and to stimulate the contraction of smooth muscle (Rubanyi and Balogh, (1982) Am J. Obstet. Gynecol. 142:1016-1020). Nickel, which is a component of asbestos, has been suggested as the tumor inducing component of asbestos (Louria et al., (1972) Annals of Internal Medicine 76:307-319; Gross et al., (1967) Environ. Health 15:343-355). Numerous investigators have studied the toxicological effects of nickel including Holti, (1974)Clin. Allergy 4:437-438; Novelli et al., (1988) Bol. Estud. Med Biol., Mex. 36:35-42; Knight et al., (1987) Ann. Clin. Lab. Sci. 17(4) 275; Edoute et al., (1986) Federation Proceedings 45(3): 1410; Leach et al., (1984) Ann. Clin. Lab. Sci. 14(5): 414-415; Oskarsson et al., (1981) Ann. Clin. Lab. Sci. 11(2):165-172; Blackburn and Highsmith, (1990) Am. J. Physiol. 258:C1025-C1030; Knight et al., (1991) Ann. Clin. Lab. Sci. 21(4):275-283; Sarkar, (1984) in Nickel in The Human Environment, International Agency for Research on Cancer, Lyon, France; and Kilburn et al., (1990) Am. J. Indust. Med. 17:607-615.
Nickel poisoning can result from direct contact with nickel containing metal objects such as needles (Sunderman, (1983) Ann. Clin. Lab. Sci. 13(1):1-4) or by contact with solutions containing dissolved nickel (Fisher, (1978) Current Contact News 22(5):544-550). The solutions where nickel poisoning can be a potential hazard are for the most part large volume body solutions. Such solutions include dialysis solutions (Sunderman, (1983) Ann. Clin. Lab. Sci. 13(1):1-4), human albumin solutions (Sunderman, (1983) Ann. Clin. Lab. Sci. 13(1):14; Koppel et al., (1988) Clin. Tox. 26:337-356; Tabata and Sarkar, (1992) J. Inorg. Chem. 45:93-104; Lucassen and Sarkar, (1979) J. Tox. Env. Health 5:897-905; Morgan, (1978) Biochimica Biophysica Acta 533:319-333; Callan and Sunderman, (1973) Res. Comm. Chem. Path. Pharm. 5(2):459-472), radiographic contrast medium (Leach and Sunderman, (1987) Ann. Clin. Lab. Sci. 17(3):137-144; Leach and Sunderman, (1986) Ann. Clin. Lab. Sci. 16(4):327-328), and total parenteral nutrition solutions (Berner et al., (1989) Am. J. Clin. Nutr. 50:1079-1083; Gramm et al., (1987) Infusiontherapie 14:290-294; Nielsen, (1984) Bull. N.Y. Acad. Med. 60(2)177-195) and blood products (Gramm et al., (1987) Infusiontherapie 14:290-294; Center for Biological Evaluation and Research, (1991) Transfusion 31(4): 369-371). Marshall et al. ((1993) in Blood Substitutes and Oxygen Carriers, Chang ed., Marcel Dekker, Inc., New York, pp. 267-270) conducted a trace element analysis of diaspirin cross-linked hemoglobin solutions, measuring the levels of 23 trace metals. They concluded that calcium, magnesium, zinc and iron were the only elements present at high enough levels to be detected, while 19 other metals could not be detected (Note that 24 metals were said to be measured, but results are only shown for 23).
The source of nickel contamination in large volume body solutions may originate from metals present in the starting materials and from process contamination (Marshall et al., (1993) in Blood Substitutes and Oxygen Carriers, Chang ed., Marcel Dekker, Inc., New York, pp. 267-270). There is evidence that leaching from stainless steel equipment increases the nickel content of solutions that come in contact with such equipment (Sunderman, (1983) Ann. Clin. Lab. Sci. 13(1):1-4). Some nickel can be airborne or in water sources allowing contamination of starting materials. For example, albumin has a high affinity for nickel so that any material using albumin is likely to contain some nickel (Sarkar, (1984) in Nickel in The Human Environment, International Agency for Research on Cancer, Lyon, France).
There are methods available for attempting to remove nickel from various solutions, but the success of a particular method for a particular solution is unpredictable. For example, various chelating resins have been used to separate various metals from a solution, including nickel, although many times such separation is effective at very low pH making it potentially damaging to proteins (e.g., hemoglobin) that may be in the solution (Figura and McDuffie, (1977) Anal. Chem. 49:1950-1953; Darnall et al., (1986) Envir. Sci. Tech. 20:206-208; Vernon, (1977) Chem. and Industry 15:634-637; Moyers and Fritz, (1977) Anal. Chem. 49:418-423; yip et al., (1989) Anal. Biochem. 183:159-171; U.S. Pat. No. 4,952,684; see Example 3).
Ethylenedinitrilo tetraacetate (EDTA) has been used as a chelating agent, but until the present invention it has not been used alone in solution to remove nickel from a protein solution containing nickel. EDTA has been used as a ligand in derivatized agarose chromatography to remove calcium (Serda and Henzel, (1991) J. Biol. Chem. 266:7291-7299) and it has been used as part of an affinity labelled chelating complex to introduce a probe into a protein or nucleotide system or as a gel to remove calcium and lanthanide ions from the binding protein parvalbumin (Haner et al., (1984) Archives Biochem. Biophys. 231:477-486; Haner et al., (1984) Anal. Biochem. 138:229-234). EDTA has also been observed to inhibit the binding of cadmium, copper, lead and zinc to Ca-Chelex chelating columns (Figura and McDuffie, (1977) Anal. Chem. 49:1950-1953).